Published online before print June 28, 2002, 10.1148/radiol.2242011039
(Radiology 2002;224:598-602.)
© RSNA, 2002
Quantifying Sodium in the Human Wrist in Vivo by Using MR Imaging1
Arijitt Borthakur, PhD,
Erik M. Shapiro, PhD,
Sarma V. S. Akella, PhD,
Alexander Gougoutas, BA,
J. Bruce Kneeland, MD and
Ravinder Reddy, PhD
1 From the Department of Radiology, University of Pennsylvania, B1 Stellar-Chance Laboratories, 422 Curie Blvd, Philadelphia, PA 19104-6100. Received June 13, 2001; revision requested August 6; revision received December 3; accepted January 22, 2002. This work was performed at an NIH-supported resource center (NIH RR02305) and supported by grants R01-AR45242 and R01-AR45404 from National Institutes of Arthritis, Musculoskeletal and Skin Diseases. Address correspondence to A.B. (e-mail: ari@mail.mmrrcc.upenn.edu).
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ABSTRACT
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The authors quantified sodium content in the wrist joints of six healthy volunteers with no known history of arthritis or pain. Average sodium concentrations ranged from 115 to 150 mmol/L in noncartilaginous regions and from 200 to 210 mmol/L in cartilaginous regions. The feasibility of quantifying sodium in vivo was demonstrated. This method has potential applications in monitoring the integrity of cartilaginous tissue in vivo.
© RSNA, 2002
Index terms: Cartilage, MR, 434.121412, 434.12146 • Magnetic resonance (MR), sodium studies, 434.121412, 434.12146 • Wrist, MR, 434.12146
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INTRODUCTION
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Osteoarthritis, a progressive disease of articular cartilage, is associated with severe joint pain and immobilization. More than 95% of the volume of articular cartilage is composed of an extracellular matrix of collagen, proteoglycans, and water. The early stage of osteoarthritis is primarily associated with a loss of proteoglycans, changes in water content, and minimal changes in collagen content and structure (1,2). Proton magnetic resonance (MR) imaging performed with routine clinical sequences can depict the macroscopic changes of articular cartilage more accurately than can other imaging modalities (3,4) but is insensitive to early biochemical changes in patients with arthritis (5). Contrast material–enhanced proton MR imaging, in which the contrast medium is permitted to diffuse into the cartilage, has been used to measure proteoglycan content; however, due to the variation in negatively charged gadopentetate dimeglumine relaxivity with change in the macromolecular content, quantitation of proteoglycans with this method may be problematic (6–8).
Another promising method for measuring proteoglycan content is sodium MR imaging. It has been shown that sodium MR imaging provides direct spatial maps of proteoglycan content in cartilage (9–12). Sodium MR imaging of the wrist has potential for depicting early degeneration associated with osteoarthritis. Furthermore, the MR imaging signal-to-noise ratio can be improved by decreasing sources of electromagnetic noise and by increasing the ratio of volume of the object inside the MR radio-frequency (RF) coil to total volume of the coil. This is achieved by reducing the size of the RF coil and by placing only the region of the subject that is being imaged within the coil. Therefore, there is a gain in sensitivity associated with imaging peripheral sites, such as the wrist, enabling an increase in image quality.
The purpose of this study was to demonstrate the feasibility of performing sodium MR imaging of human wrist joints in vivo and to quantify sodium content of these joints by generating sodium concentration maps.
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Materials and Methods
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Subjects
The study included six volunteers (two women, four men; age range, 21–25 years; mean age, 24 years). A physician deemed the subjects healthy after evaluating their medical history, serum pregnancy test results in women, and body weight and height. Since this was a feasibility study, we included only subjects with no known history of arthritis, wrist pain, or destructive joint disease, including osteoarthritis and rheumatoid arthritis. We excluded pregnant women and subjects with a diagnosed metabolic disorder affecting the bone, including Paget disease, hyperparathyroidism, hyperthyroidism, and osteomalacia, and subjects with implanted metal medical devices. The institutional review board of the University of Pennsylvania granted approval for the study, and informed consent was obtained from each volunteer.
MR Imaging
Sodium and proton MR images of the right wrist joint were obtained with a 4-T MR imaging system (GE Medical Systems, Milwaukee, Wis). Two custom-built 10-cm-diameter RF coils—a solenoid coil tuned to sodium frequency (45 MHz) and a quadrature birdcage coil tuned to proton frequency (172 MHz)—were used to transmit and receive. A three-dimensional (3D) fast gradient-echo sequence was used to obtain sodium MR images. Imaging parameters were 80/2.4 (repetition time msec/echo time msec), 90° flip angle, 16 x 16-cm field of view, 4.0-mm section thickness, 256 x 64 matrix, 16 signals acquired, and a total imaging time of 22 minutes for a data set of 16 sections. Proton images were obtained in the same locations by using a 3D fat-suppressed spoiled gradient-echo sequence with the following parameters: 20/60, 45° flip angle, 8 x 8-cm field of view, 1.5-mm section thickness, 512 x 256 matrix, one signal acquired, and a total imaging time of 8 minutes for a data set of 28 sections. As previously described (11), sodium quantitation was performed by simultaneously imaging phantoms containing different concentrations of sodium (100, 150, 200, and 250 mmol/L) in 10% wt/vol agarose gel. Sodium T1 and T2 of the phantoms were previously determined to be similar to those of bovine articular cartilage.
In vivo imaging requires careful positioning of the subject’s anatomy and use of methods to minimize subject motion during the long acquisitions. Our RF coils were mounted on a platform that was attached to the bed of the MR imager. By placing a peg between the subject’s thumb and forefinger and strapping the wrist to the coil with a wristband, we were able to minimize wrist motion inside the coil (Fig 1).
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Figure 1. Sodium RF coil used in our experiments. The location of the viewing window facilitated accurate positioning of the wrist inside the coil. To minimize involuntary patient motion during imaging, we placed an adjustable peg between the thumb and forefinger, and the subject’s wrist was strapped to the coil with a wristband.
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Signal Intensity Calibration and Measurement of Sodium Content
Data processing was performed by using custom-built routines written with IDL software (RSI, Boulder, Colo). Each image in the sodium data sets was corrected for T2 decay by dividing every pixel by exp(-[echo time]/T2*). The T2* of cartilage and surrounding tissue was previously determined to be 4.5 msec. The T2* of the calibration phantoms was 9 msec. After this correction was applied, a single observer (A.B.) manually selected an elliptical region of interest (ROI) with a long axis of 20 pixels within each calibration phantom. The average signal intensity of the ROI was plotted against its known sodium concentration. A straight-line fit through the data yielded a slope and intercept that were applied to the rest of the image to convert the signal intensities (in arbitrary units) to sodium concentrations (in millimoles per liter). The correlation coefficient (R2) between the fit and the data was used as a measure of the goodness of the fit. It is known that 75% of the volume of cartilage is composed of water (13,14). Therefore, the actual sodium concentration was obtained by dividing the sodium concentration (in millimoles per liter) by 75%.
Seven ROIs within the wrist joint were manually selected on each image by a single observer (A.B.) (Fig 2). These ROIs included the (a) radiocarpal joint, (b) distal radioulnar joint, (c) ulnar collateral ligament, and the (d) scapholunate, (e) lunotriquetral, (f) scaphocapitate, and (g) capitotriquetral joints. The elliptical ROIs had a long axis of 10 pixels. Average sodium concentrations were determined for each ROI over three imaging sections. The averages were used to determine the mean and SD of sodium content in each ROI for all volunteers.
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Figure 2. Diagram of the joints of the human wrist (15). The ROIs where sodium content was measured were located in the (a) radiocarpal joint, (b) distal radioulnar joint, (c) ulnar collateral ligament, and the (d) scapholunate, (e) lunotriquetral, (f) scaphocapitate, and (g) capitotriquetral joints. The articular surfaces are white.
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Results
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The signal intensities from the calibration phantoms with known sodium contents provided meaningful calibration curves. A typical curve is shown in Figure 3. This method of signal intensity calibration provided accurate determination of sodium concentrations from the images. In all data sets, straight-line regressions resulted in high correlation between signal intensity and the known concentrations of the phantoms (R2 > 0.97, P < .01). Accurate signal intensity calibration allowed us to relate each pixel’s intensity on the MR image to its sodium concentration. In this way, we generated "sodium concentration maps" from each MR image of the wrist joint. These maps clearly show the articular cartilage surrounding the major bones of the wrist (Fig 4). The average sodium concentrations for all volunteers in the seven regions indicated in Figure 2 are provided in the Table. We observed a significantly higher concentration of sodium in cartilage (approximately 200 mmol/L in healthy tissue) than in the surrounding ligaments and synovial fluid (115–140 mmol/L). Average sodium concentrations ranged from 115 mmol/L in location 4 to 210 mmol/L in location 1 (Fig 5).
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Figure 3. An example of a calibration curve obtained from the sodium MR signal intensity of the calibration phantoms imaged alongside the wrist. The signal intensities of four agarose gel phantoms containing sodium chloride are plotted against their individual sodium concentrations (100, 150, 200, and 250 mmol/L). The first data point, the background signal intensity, is also included in the straight-line regression, resulting in a high correlation (R2 = 0.98, P < .01). The slope and intercept were used to determine the sodium concentration of every other pixel on the image.
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Figure 4. Calculated sodium concentration maps in the wrist joint of a healthy 22-year-old man. The scale at the top right indicates the sodium concentration in the tissue. Three consecutive coronal MR sections from a 3D data set of 16 sections are shown (top row). The proton MR images obtained in the same location with a 3D fat-suppressed spoiled gradient-echo sequence are shown for comparison (bottom row). The sodium content in the wrist joint of this individual ranged from 100 to 220 mmol/L.
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Figure 5. Graph shows average sodium concentrations in the locations indicated in Figure 2. Locations containing cartilage are shown in black, whereas noncartilaginous regions (eg, ligaments and synovial fluid) are shown in gray. Maximum sodium concentration was observed in the radiocarpal joint (210 mmol/L), while the region between the scaphoid and lunate bones showed the lowest concentration of sodium (120 mmol/L).
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Discussion
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Proteoglycans are an important constituent of the extracellular matrix of articular cartilage. The loss of proteoglycans and collagen results in the total mechanical failure of cartilage. Proteoglycan macromolecules maintain a fixed negative charge density that contributes to tissue resilience. Fixed negative charge density results from the net negative charge of COO- and the SO
groups in the glycosaminoglycan side chains of proteoglycan molecules (16). Positively charged sodium ions are attracted by the fixed negative charge density to maintain electroneutrality. The sodium content of cartilage can be directly correlated with its fixed negative charge density, and, therefore, with proteoglycan content (17) in the following way. If we assume that ion concentrations in the tissue maintain electroneutrality, then ideal Donnan equilibrium conditions allow the calculation of the fixed negative charge density of tissue by means of the following equation (9):
where FCD is the fixed negative charge density, [Na+]b is the sodium concentration of the bathing solution (ie, approximately 150 mmol/L in synovial fluid), and [Na+]t is the tissue sodium concentration measured by means of sodium MR imaging.
Furthermore, sodium T1 and T2 increase with proteoglycan depletion (18). For these reasons, sodium MR imaging may be of value in assessing the chemical and physiologic changes in cartilage during the early stages of arthritis. More important, sodium MR imaging is advantageous in investigating pathologic conditions in which the changes in sodium MR properties of the tissue of interest are more pronounced than the changes in relaxation times and water content. However, the considerably lower sodium concentration in tissues compared with that in water and a fourfold smaller gyromagnetic ratio result in a dramatically lower signal-to-noise ratio for sodium MR imaging than for proton MR imaging. Therefore, it is necessary to reduce resolution to gain sensitivity. However, the short T1 of sodium in cartilage, which we previously measured as approximately 20 msec, allows for rapid signal acquisition, which partially offsets the loss in signal-to-noise ratio per unit of time.
During data analysis, we assumed a water volume fraction of 75% throughout the cartilage. The accuracy of sodium quantitation may be increased, however, by measuring the volume fraction of water in the tissue on a pixel-by-pixel basis. To this end, we are investigating a strategy similar to our sodium quantitation method (19) to determine the water volume fraction in cartilage in vivo. It should be noted that because of the thin nature of the cartilage, the irregular shape of the carpal bones, and the relatively thick section thickness used for sodium MR imaging, it is expected that partial volume effects will lead to an underestimation of sodium content. Work is in progress to determine the extent of this underestimation. For the same reasons, it may be difficult to distinguish between synovial fluid (if any) and cartilage. Since the T1 of synovial fluid (approximately 60 msec) is much greater than that of cartilage, however, a repetition time of 80 msec will attenuate the signal from fluid on these images.
Accurate sodium content measurement in vivo is limited by the lack of an adequate reference standard. We have confidence in our measurements, however, because we have previously validated our method in vitro. In that experiment, we compared measurements of sodium content in bovine patellar cartilaginous specimens by means of three independent methods: MR spectroscopy of whole cartilaginous plugs, MR spectroscopy of liquefied cartilage in concentrated hydrochloric acid, and inductively coupled plasma emission spectroscopy. All three techniques provided nearly identical results (11). Furthermore, the sensitivity of our imaging technique to proteoglycan content in cartilage was also verified in experiments in which bovine patellar specimens underwent enzymatic depletion of proteoglycans. We observed that the change in sodium content (measured with sodium MR imaging) correlated with the loss of proteoglycans (measured with a biochemical assay) resulting from the degradation of cartilage (12). These experiments have allowed for the use of this technique as a nondestructive assay of sodium in cartilage in vitro (20). Following validation, perhaps in an animal model, this technique will lead to a nondestructive and noninvasive measurement of cartilage tissue integrity in vivo.
In conclusion, the results of this study demonstrate that it is feasible to quantify sodium in the human wrist in vivo. Sodium concentration averages around 210 mmol/L in cartilage and 115–140 mmol/L in other tissues. We believe our method will facilitate the assessment of proteoglycans in vivo, and, therefore, should provide a quantitative and noninvasive determination of cartilage integrity before macroscopic defects become evident.
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ACKNOWLEDGMENTS
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We thank John S. Leigh, PhD, for his encouragement and support.
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FOOTNOTES
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Abbreviations: RF = radio frequency,
ROI = region of interest,
3D = three-dimensional
Author contributions: Guarantor of integrity of entire study, R.R.; study concepts and design, R.R.; literature research, A.B.; clinical and experimental studies, all authors; data acquisition, all authors; data analysis/interpretation, A.B.; statistical analysis, A.B.; manuscript preparation and definition of intellectual content, A.B.; manuscript editing, all authors; manuscript revision/review, A.B.; manuscript final version approval, all authors.
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TOP
ABSTRACT
INTRODUCTION
